Chemotherapy
Summary
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References
Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology.
Life Sci. 1995;56(23-24):2097-2102.
Abstract: Delta-8-tetrahydrocannabinol (delta-8-THC), a cannabinoid with lower psychotropic potency than the main Cannabis constituent, delta-9-tetrahydrocannabinol (delta-9-THC), was administered (18 mg/m2 in edible oil, p.o.) to eight children, aged 3-13 years with various hematologic cancers, treated with different antineoplastic drugs for up to 8 months. The total number of treatments with delta-8-THC so far is 480. The THC treatment started two hours before each antineoplastic treatment and was continued every 6 hrs for 24 hours. Vomiting was completely prevented. The side effects observed were negligible.
Albini A, D'Agostini F, Giunciuglio D, Paglieri I, Balansky R, De Flora S. Inhibition of invasion, gelatinase activity, tumor take and metastasis of malignant cells by N-acetylcysteine. Int J Cancer 1995 Mar 29;61(1):121-129.
Abstract: The thiol N-acetylcysteine (NAC) is currently considered one of the most promising cancer chemopreventive agents by virtue of its multiple and coordinated mechanisms affecting the process of chemical carcinogenesis. Recent studies have shown that an unpaired cysteine residue in the propeptide plays a key role in inactivation of latent metastasis-associated metalloproteinases: the present study was designed to assess whether NAC could also affect tumor take, invasion and metastasis of malignant cells. As assessed by zymographic analysis, NAC completely inhibited the gelatinolytic activity of type-IV collagenases in the cells tested (gelatinases A and B). Moreover, NAC was efficient in inhibiting the chemotactic and invasive activities of tumor cells of human (A2058 melanoma) and murine origin (K1735 and B16-F10 melanoma cells as well as C87 Lewis lung carcinoma cells) in Boyden-chamber assays, which are predictive of the invasive and metastatic properties. Reduced glutathione (GSH) had a similar, although less effective activity. The number of lung metastases decreased sharply when B16-F10 murine melanoma cells, injected i.v. into nude mice, were pre-treated with NAC and resuspended in medium supplemented with 10 mM NAC. In other experiments NAC was given in drinking water, starting 48-72 hr before subcutaneous inoculation of either B16-F10 cells or of their highly metastatic variant B16-BL6, or intramuscular injection of LLC cells. In all experiments NAC treatment decreased the weight of the locally formed primary tumor and produced a dose-related delay in tumor formation. Spontaneous metastasis formation by B16-F10 and B16-BL6 tumors was slightly yet significantly reduced by oral administration of NAC. However, this was not observed for Lewis lung tumors. These data indicate that NAC affects the process of tumor-cell invasion and metastasis, probably due to inhibition of gelatinases by its sulfhydryl group, with the possible contribution of other mechanisms, including the potent antioxidant activity of this thiol.
Andresen GV, Birch LL, Johnson PA. The scapegoat effect on food aversions after chemotherapy.
Cancer 1990 Oct 1;66(7):1649-1653.
Abstract: The effects of consuming a novel food (halva) versus a familiar food (cookies) before gastrointestinal (GI) toxic chemotherapy on patients' preference for familiar foods consumed after chemotherapy treatment were compared. The development of aversions to the novel and familiar foods was also assessed. Patients with a history of posttreatment nausea consumed either a novel or a familiar food before chemotherapy and were asked to keep a food record through the next breakfast and to rate their preference for these foods. Patients who consumed halva before treatment were significantly more likely to increase their ratings for foods consumed after chemotherapy than patients who consumed familiar cookies. Aversions to the novel food were significantly more frequent than aversions to the familiar food. These findings provide evidence that a novel but not a familiar food consumed before chemotherapy can act as a scapegoat to prevent items in the regular diet consumed after chemotherapy from decreasing in preference. Providing patients with a novel food before chemotherapy is a useful clinical intervention to reduce the likelihood of forming aversions to familiar foods consumed after chemotherapy.
Barber MD, Ross JA, Preston T, Shenkin A, Fearon KC. Fish oil-enriched nutritional supplement attenuates progression of the acute-phase response in weight-losing patients with advanced pancreatic cancer.
J Nutr 1999 Jun;129(6):1120-1125.
Abstract: The presence of an acute-phase protein response (APPR) has been suggested to shorten survival and contribute to weight loss in patients with pancreatic cancer. Fatty acids derived from fish oil have been shown to alter proinflammatory cytokine production and acute-phase protein synthesis in vitro. The present study was designed to determine the effects of a fish oil-enriched nutritional supplement on the concentrations of a range of individual acute-phase proteins (APP) in patients with advanced pancreatic cancer. In a sequential series, 18 patients with pancreatic cancer received the supplement (providing 2 g eicosapentaenoic acid and 1 g docosahexaenoic acid/d) for 3 wk while another 18 received full supportive care alone. Six healthy subjects served as additional controls. Acute-phase proteins were measured before and after the 3-wk intervention period in cancer patients. At baseline, albumin, transferrin and pre-albumin were significantly reduced and fibrinogen, haptoglobin, alpha-1-acid glycoprotein, alpha-1-antitrypsin, ceruloplasmin and C-reactive protein (CRP) were significantly elevated in the cancer patients compared with healthy controls, reflecting their roles as negative and positive acute phase proteins, respectively. In the supplemented cancer group, the only significant change in APP concentrations over the 4-wk study period was an increase in transferrin. In the control cancer group there were further significant reductions in albumin, transferrin and pre-albumin, and a significant increase in CRP concentration. These results suggest that many positive and negative APP are altered in advanced pancreatic cancer. The APPR tends to progress in untreated patients but may be stabilized by the administration of a fish oil-enriched nutritional supplement. This may have implications for reducing wasting in such patients.
Bartoshuk LM. Chemosensory alterations and cancer therapies. NCI Monogr 1990;(9):179-184.
Bernstein IL. Learned food aversions in the progression of cancer and its treatment.
Ann N Y Acad Sci 1985;443:365-380.
Bokemeyer C, Fels LM, Dunn T, Voigt W, Gaedeke J, Schmoll HJ, Stolte H, Lentzen H. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer 1996 Dec;74(12):2036-2041.
Abstract: Cisplatin is one of the most active cytotoxic agents in the treatment of testicular cancer, but its clinical use is associated with side-effects such as ototoxicity, neurotoxicity and nephrotoxicity. Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes, such as L-alanine-aminopeptidase (AAP), and magnesium. In the current study, the flavonoid silibinin was used as a nephroprotectant for cisplatin-induced nephropathy in a rat animal model. Infusion of silibinin before cisplatin results in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Silibinin given alone had no effect on renal function. In order to exclude an inhibition of the anti-tumour activity of cisplatin and 4-hydroperoxy-ifosfamide by co-administration of silibinin, in vitro studies were performed in three established human testicular cancer cell lines. Dose-response curves for cisplatin (3-30 000 nmol) combined with non-toxic silibinin doses (7.25 x 10(-6) or 7.25 x 10(-5) mol l-1) did not deviate significantly from those of cisplatin alone as measured by relative cell survival during a 5 day assay using the sulphorhodamine-B staining technique. Also silibinin did not influence the cytotoxic activity of 4-hydroperoxy-ifosfamide (30-10 000 nmol) in vitro. In summary, these in vitro data rule out a significant inhibition of the anti-tumour activity of the major nephrotoxic components, cisplatin and 4-hydroperoxy-ifosfamide, by co-administration of silibinin in a human germ cell tumour cell line model. Together with these demonstrated cytoprotection effects in the rat animal model, these data form the basis for a randomised clinical trial of silibinin for the protection of cisplatin-associated nephrotoxicity in patients with testicular cancer.
Broberg DJ, Bernstein IL. Candy as a scapegoat in the prevention of food aversions in children receiving chemotherapy.
Cancer 1987 Nov 1;60(9):2344-2347.
Abstract: The effectiveness of a method for reducing the incidence of chemotherapy-induced learned food aversions was examined. Candy (coconut or rootbeer Lifesavers) was used as a scapegoat and given between the consumption of a meal and the administration of chemotherapy to determine whether this would lead to a greater willingness to consume items in that meal at a future test. This procedure produced evidence that the scapegoat had a significant protective effect: children were twice as likely to eat some portion of their test meal at the time of assessment if they had received the scapegoat at conditioning than when there was no intervention. Thus, the consumption of strongly flavored candies before chemotherapy appears to be a simple and effective way to reduce the impact of chemotherapy on preference for normal menu items.
Calhoun SR, Galloway GP, Smith DE, Abuse potential of dronabinol (Marinol). J Psychoactive Drugs
1998 Apr-Jun;30(2):187-196.
Abstract: Dronabinol is an oral form of delta-9-tetrahydrocannabinol indicated for treatment of anorexia associated with weight loss in individuals with AIDS, and nausea and vomiting associated with cancer chemotherapy. The authors reviewed the literature and conducted surveys and interviews among addiction medicine specialists, oncologists, researchers in cancer and HIV treatment, and law enforcement personnel to determine the abuse liability of dronabinol. There is no evidence of abuse or diversion of dronabinol. Available prescription tracking data indicates that use remains within the therapeutic dosage range over time. Healthcare professionals have detected no indication of "scrip-chasing" or "doctor-shopping" among the patients for whom they have prescribed dronabinol. Cannabis-dependent populations, such as those treated in our Clinic and seen by the addiction medicine specialists we interviewed, have demonstrated no interest in abuse of dronabinol. There is no street market for dronabinol, and no evidence of any diversion of dronabinol for sale as a street drug. Furthermore, dronabinol does not provide effects that are considered desirable in a drug of abuse. The onset of action is slow and gradual, it is at most only weakly reinforcing, and the overwhelming majority of reports of users indicate that its effects are dysphoric and unappealing. This profile of effects gives dronabinol a very low abuse potential.
Das UN, Madhavi N, Sravan Kumar G, Padma M, Sangeetha P. Can tumour cell drug resistance be reversed by essential fatty acids and their metabolites?
Prostaglandins Leukot Essent Fatty Acids 1998 Jan;58(1):39-54.
Tumour cell drug resistance is a major problem in cancer chemotherapy. Essential fatty acids have been shown to be cytotoxic to a variety of tumour cells in vitro. But, the effect of these fatty acids on tumour cell drug resistance has not been well characterized. Gamma-linolenic acid (GLA) of the n-6 series and eicosapentaenoic acid (EPA) of the n-3 series potentiated the cytotoxicity of anti-cancer drugs: vincristine, cis-platinum and doxorubicin on human cervical carcinoma (HeLa) cells in vitro. Alpha-linolenic acid (ALA), GLA, EPA and docosahexaenoic acid (DHA) enhanced the uptake of vincristine by HeLa cells. In addition, DHA, EPA, GLA and DGLA were found to be cytotoxic to both vincristine-sensitive (KB-3-1) and -resistant (KB-ChR-8-5) human cervical carcinoma cells in vitro. Pre-incubation of vincristine-resistant cells with sub-optimal doses of fatty acids enhanced the cytotoxic action of vincristine. GLA, DGLA, AA, EPA and DHA enhanced the uptake and inhibited the efflux of vincristine and thus, augmented the intracellular concentration of the anti-cancer drug(s). Fatty acid analysis of KB-3-1 and KB-ChR-8-5 cells showed that the latter contained low amounts of ALA, GLA, 22:5 n-3 and DHA in comparison to the vincristine-sensitive cells. The concentrations of GLA and DHA were increased 10-15 fold in the phospholipid, free fatty acid and ether lipid cellular lipid pools of GLA and DHA treated cells. These results coupled with the observation that various fatty acids can alter the activity of cell membrane bound enzymes such as sodium-potassium-ATPase and 5'-nucleotidase, levels of various anti-oxidants, p53 expression and the concentrations of protein kinase C suggest that essential fatty acids and their metabolites can reverse tumour cell drug-resistance at least in vitro.
de Blasio F, Forgione L, Marrazzo R. N-acetyl cysteine (NAC) in preventing nausea and vomiting induced by chemotherapy in patients suffering from inoperable non small cell lung cancer (NSCLC).
Chest 1996;110(4, Suppl):103S.
Abstract: Among therapeutic strategies for inoperable NSCLC chemotherapy is still considered as the first choice even if with its controversies and debates. In fact, several studies demonstrated the effectiveness of chemotherapy vs best supportive care either in terms of survival, cost and quality of life. Nevertheless, the limiting factor of chemotherapy is represented by side effects among which nausea and vomiting. Several and effective new drugs have been proposed to solve this problem but at very high cost. AIM: The aim of the study is to evaluate the possible therapeutic role of NAC in the prevention of chemotherapy induced nausea and vomiting in patients suffering from inoperable NSCLC. METHODS: Twentytwo consecutive patients (17 male; mean age 63.2 yrs + 2.5) affected by inoperable NSCLC treated with chemotherapy were evaluated. The chemotherapy regimen (cyclophosphamide 400mg/m2; epirubicin 40 mg/m2; carboplatin 200 mg/m2 q8 days) was administered iv. in one day for six courses. Seventeen of these patients were randomly selected to further receive an oral daily dosage of 1800 mg (three tablets) of NAC. Furthermore, each of the patients received granisetron 3mg/iv on the day of the therapy, and chemotherapy induced nausea and vomiting data collected according to WHO, for five days after each course. RESULTS: At the end of the treatment patients receiving both chemotherapy and NAC showed a lower incidence of nausea and vomiting (13% vs 28%) and a low WHO intensity grade (0.8 + 0.3 vs 1.7 + 0.6) since the first day after the therapy when compared to patients receiving chemotherapy alone. CONCLUSIONS: In addition to antiemetic drugs, NAC oral administration of 1.800 mg demonstrates to prevent the incidence and the intensity of chemotherapy induced gastrointestinal side effects in patients suffering from inoperable NSCLC.
Delneste Y, Jeannin P, Potier L, Romero P, Bonnefoy JY. N-acetyl-L-cysteine exhibits antitumoral activity by increasing tumor necrosis factor alpha-dependent T-cell cytotoxicity.
Blood 1997 Aug 1;90(3):1124-1132.
Abstract: Because of its anticarcinogenic and antimutagenic properties, N-acetyl-L-cysteine (NAC) has been proposed for cancer treatment. Here we present a mechanism of action for NAC in cancer. Our data show that NAC (1) induces an early and sustained increase of membrane tumor necrosis factor alpha (TNF alpha) expression on human stimulated-peripheral blood (PB) T cells and (2) increases membrane TNF-RI and TNF-RII on tumoral cell lines and on T cells after stimulation. These effects result from an early inhibition of both TNF alpha and TNF-R shedding, as well as a later increase of the respective mRNA expression. Consequently, NAC confers cytotoxic properties to human PB T cells through a membrane TNF alpha-dependent pathway. In vivo, NAC given orally inhibits tumor appearance in more than a third (18 out of 50) B6D2F1 mice injected with L1210 lymphoma cells. Spleen cells from protected mice killed L1210 lymphoma cells in vitro in a membrane TNF alpha-dependent manner. Furthermore these mice were resistant to a second inoculation of L1210 cells without further treatment with NAC. Thus, NAC exhibits a potent antitumoral activity by modulating TNF alpha and TNF-R processing without showing any in vitro and in vivo toxicity.
Domenighetti G, Quattropani C, Schaller MD. [Therapeutic use of N-acetylcysteine in acute lung diseases].
Rev Mal Respir 1999 Feb;16(1):29-37. [Article in French]
Abstract: Oxidants play a key role in disease processes, particularly in the detrimental mechanisms leading to tissue damage in certain forms of acute lung injury. A number of mediators contribute to the pathologic response in ARDS, SIRS or hyperoxia-induced pulmonary damage. One of the most important detrimental factors is the generation and activation of highly reactive oxygen species which are leading factors implicated in the process of tissue damage. N-acetylcysteine (NAC) is a free radical scavenger and might access the endothelial cell thus increasing intracellular glutathione (GSH) stores. Different studies have demonstrated that NAC might be a promising compound either for the prevention or the treatment of acute lung damages such as ARDS. However, the true beneficial effect so far reported in several clinical and experimental studies contrasts with some contradictory and intriguing aspects, probably because the significance of a direct in vivo antioxidative effect of this compound remains to be established in humans. Thus, the mode of action of NAC may not be the same in different pathologies and clinical situations. More research into the mechanisms of action of this unique xenobiotic substance may offer a clue for elucidating these controversies.
Dreizen S, McCredie KB, Keating MJ, Andersson BS. Nutritional deficiencies in patients receiving cancer chemotherapy.
Postgrad Med 1990 Jan;87(1):163-167, 170.
Abstract: Cancer often causes malnutrition and specific vitamin and protein deficiencies. Chemotherapy also causes deficiencies by promoting anorexia, stomatitis, and alimentary tract disturbances. Antimetabolite drugs in particular inhibit synthesis of essential vitamins, purines, and pyrimidines. Because vitamin levels in the blood are often nondiagnostic, nutritional deficiency is identified almost exclusively on the basis of clinical signs and symptoms and the patient's response to therapy. Signs and symptoms of cachexia and hypoalbuminemia are common in patients with advanced cancer. Deficiencies of vitamins B1, B2, and K and of niacin, folic acid, and thymine also may result from chemotherapy. Nutritional deficiencies are chemically correctable; however, the tumor must be eradicated to relieve cachexia.
Friedman T, Slayton WB, Allen LS, Pollock BH, Dumont-Driscoll M, Mehta P, Graham-Pole J. Use of alternative therapies for children with cancer.
Pediatrics. 1997 Dec;100(6):E1.
Abstract: Objective. To compare the use of alternative therapy (AT) in families of children with cancer with its use in those with routine pediatric conditions. Background and Rationale. AT refers to healing practices such as therapeutic massage, acupuncture, and use of medicinal herbs that have become increasingly popular with the general public, but are not widely accepted by the medical profession. Although studies have investigated the use of AT in the families of both healthy children and children with cancer, no comparison of the incidence of its use between these two populations has been published. We hypothesized that AT was used more frequently among the families of children with cancer. Methods. Using a prevalence survey design, we interviewed 81 parents of children with cancer attending a pediatric hematology/oncology clinic and 80 parents of children attending a continuity care clinic for routine check-ups and acute care. We explored the types of AT being used, the reasons for its use, and the frequency with which it was discussed with the patient's physician. Results. 1) Overall, 65% of the cancer group were using AT, compared with 51% of the control group. This was not statistically significant. 2) Prayer, exercise, and spiritual healing were three AT practices most often used by the cancer group, and prayer, massage, and spiritual healing by the control group. 3) Discussion of AT with the physician varied according to group, with 53% of the cancer patients discussing its use; income level, with 59% of parents in the higher income group discussing its use; and ethnicity, with 47% of whites discussing its use. Conclusion. Use of AT is not limited to the families of children with life-challenging illnesses, but is commonly used by those of children with routine pediatric problems. Pediatricians need to be aware that their patients may not tell them about AT practices they are using in addition to prescribed treatment.
Fujiwaki R, Iida K, Ohnishi Y, Watanabe Y, Ryuko K, Takahashi K, Miyazaki K. Intra-arterial neoadjuvant chemotherapy followed by radical surgery and radiotherapy for stage IIb cervical carcinoma.
Anticancer Res 1997 Sep-Oct;17(5B):3751-3755.
Abstract: BACKGROUND: The role of intra-arterial neoadjuvant chemotherapy (NAC) in the management of cervical carcinoma has not been established. The aim of this study was to determine whether pre-operative intra-arterial NAC is effective or not in patients with stage IIb cervical carcinoma. PATIENTS AND METHODS: A total of 28 patients with stage IIb cervical carcinoma (diameter > 4 cm) were treated with one cycle of intra-arterial NAC (cisplatin 70 mg/m2, and peplomycin sulfate 30 mg/m2 or doxorubicin 30 mg/m2) followed by radical surgery and post-operative radiotherapy. Immediate response, toxicity, survival, and prognostic factors for survival were evaluated. RESULTS: The overall clinical response rate was 79% (22/28) with a complete response in 1 patient (4%). Radical hysterectomy with pelvic lymphadenectomy was feasible in 25 patients (89%) 4 weeks after chemotherapy. Toxicity were generally mild, and there were no intraoperative complications related to intra-arterial NAC. The estimated 2- and 5-year survival rates for the entire group were 93% and 80%, respectively, with a median followup time in survivors of 62 months. Univariate analysis showed the following to be significantly related to survival: histologic type, PCNA index, clinical response to intraarterial NAC, and lymph node metastasis. Survival was not significantly related to age, grade of differentiation, serum level of squamous cell carcinoma antigen, p53 protein expression, or residual parametrial involvement. Multivariate Cox's proportional hazard analysis showed that only the histologic type significantly influenced survival (p = 0.0007). The estimated 2- and 5-year survival rates were 100% and 94% for patients with squamous cell carcinoma, and 75% and 50% for those with adenocarcinoma. CONCLUSIONS: Intra-arterial NAC followed by surgery and radiotherapy appeared to be effective in treating patients with stage IIb cervical squamous cell carcinoma, but was not as effective in patients with stage IIb cervical adenocarcinoma.
Gaedeke J, Fels LM, Bokemeyer C, Mengs U, Stolte H, Lentzen H. Cisplatin nephrotoxicity and protection by silibinin.
Nephrol Dial Transplant 1996 Jan;11(1):55-62.
Abstract: BACKGROUND. The anticancer drug cisplatin is know to have toxic side-effects on different segments of the nephron. The flavonoid silibinin has previously been shown to be protective in models of hepatotoxicity. The aim of the present study was to evaluate, whether silibinin can also ameliorate alterations in renal glomerular and tubular function and tubular morphology induced by cisplatin. METHODS. In a rat model renal damage was induced by a single injection of cisplatin (5 mg/kg body weight). The protective effects of silibinin were studied in rats that received the flavonoid (200 mg/kg body weight, i.v.) 1 h prior to the administration of cisplatin. Kidney function was monitored by analysing urinary markers of glomerular and tubular function over a period of 11 days. Animals of a second group, with identical treatment, were sacrificed 4 days after drug application for an evaluation of tubular morphology at the light-microscopical level. RESULTS. Administration of cisplatin caused a decline in kidney function within a day following treatment. Symptoms observed were for example decreases in creatinine clearance and increases in proteinuria, in the urinary activity of the proximal tubular enzymes alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase and in renal magnesium wasting. The effects of cisplatin on creatinine clearance and proteinuria were totally prevented by a pretreatment of the animals with silibinin. Impairment of proximal tubular function was ameliorated, that is enzymuria and magnesium wasting was less pronounced. Silibinin alone had no effect on kidney function. Treatment with silibinin distinctly diminished morphological alterations observed in the S3-segment of the proximal tubule 4 days after cisplatin administration. CONCLUSION. The effects of cisplatin on glomerular and proximal tubular function as well as proximal tubular morphology could totally or partly be ameliorated by silibinin. It is concluded the silibinin can act as a nephroprotectant and it is suggested that it could have beneficial effects on the kidney in clinical settings.
Gillissen A, Nowak D. Characterization of N-acetylcysteine and ambroxol in anti-oxidant therapy.
Respir Med 1998 Apr;92(4):609-623. (Review)
Hacker B, Medon PJ. Cytotoxic effects of Eleutherococcus senticosus aqueous extracts in combination with N6-(delta 2-isopentenyl)-adenosine and 1-beta-D-arabinofuranosylcytosine against L1210 leukemia cells.
J Pharm Sci 1984 Feb;73(2):270-272.
Abstract: The use of the aqueous extracts of Eleutherococcus senticosus in combination with either cytarabine or N6-(delta 2-isopentenyl)-adenosine gave additive antiproliferative effects against L1210 murine leukemia. The ED50 for E. senticosus root extracts against L1210 cells was approximately 75 micrograms/mL. E. senticosus appears to be potentially useful for reducing the concentration of conventional antimetabolites used for their antiproliferative effects on tumor cells.
Henquin N, Havivi E, Reshef A, Barak F, Horn Y. Nutritional monitoring and counselling for cancer patients during chemotherapy.
Oncology 1989;46(3):173-177.
Abstract: The objective of the study was to try to monitor the nutritional status of cancer patients during chemotherapeutic treatment. Concomitantly with chemotherapeutic treatment administered to patients with cancer of the gastrointestinal tract and metastatic carcinoma of unknown origin, levels of carotene, retinol, thiamine, riboflavin, pyridoxine, iron, total protein and hemoglobin were measured in the blood periodically. In addition, anthropometric studies were performed and the nutritional status was established. A total of 19 patients were subject for final evaluation. These patients formed 3 groups according to their nutritional status (good, medium, poor). The effect of chemotherapy was correlated to the nutritional status at 3 different periods of chemotherapy. Most patients with good clinical status maintained the initial nutritional status. Half of the patients with medium nutritional status improved clinically during therapy, and patients initially with poor nutritional status further deteriorated. The levels of most vitamins decreased to a certain degree during therapy and returned to initial values thereafter. Our impression is that cancer patients might benefit from intensive ongoing personal nutritional monitoring and counselling. The results presented have a preliminary meaning because of the small number of patients included in this study.
Iigo M, Nakagawa T, Ishikawa C, Iwahori Y, Asamoto M, Yazawa K, Araki E, Tsuda H. Inhibitory effects of docosahexaenoic acid on colon carcinoma 26 metastasis to the lung.
Br J Cancer 1997;75(5):650-655.
Abstract: Unsaturated fatty acids, including n-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (C22:6, DHA) and eicosapentaenoic acid (C20:5, EPA), and a series of n-6 PUFAs were investigated for their anti-tumour and antimetastatic effects in a subcutaneous (s.c.) implanted highly metastatic colon carcinoma 26 (Co 26Lu) model. EPA and DHA exerted significant inhibitory effects on tumour growth at the implantation site and significantly decreased the numbers of lung metastatic nodules. Oleic acid also significantly inhibited lung metastatic nodules. Treatment with arachidonic acid showed a tendency for reduction in colonization. However, treatment with high doses of fatty acids, especially linoleic acid, increased the numbers of lung metastatic nodules. DHA and EPA only inhibited lung colonizations when administered together with the tumour cells, suggesting that their incorporation is necessary for an influence to be exerted. Chromatography confirmed that contents of fatty acids in both tumour tissues and plasma were indeed affected by the treatments. Tumour cells pretreated with fatty acids in vivo, in particular DHA, also showed a low potential for lung colony formation when transferred to new hosts. Thus, DHA treatment exerted marked antimetastatic activity associated with pronounced change in the fatty acid component of tumour cells. The results indicate that uptake of DHA into tumour cells results in altered tumour cell membrane characteristics and a decreased ability to metastasize.
Iino Y, Yokoe T, Maemura M, Horiguchi J, Takei H, Ohwada S, Morishita Y. Immunochemotherapies versus chemotherapy as adjuvant treatment after curative resection of operable breast cancer.
Anticancer Res 1995 Nov-Dec;15(6B):2907-2911.
Abstract: In our previous study, oral adjuvant combination chemotherapy of 5-fluorouracil, cyclophosphamide, mitomycin C, and predonisolone (FEMP) after curative resection of operable breast cancer with vascular invasion in the tumor and/or in the metastatic lymph node was found to be more effective than one course of mitomycin C or cyclic course of mitomycin C. In the present study, we have assessed the efficacy of protein-bound polysaccharide (PSK) or levamisole (LMS) in addition to FEMP. Between January 1980 and December 1990, 227 operable breast cancer patients with vascular invasion in the tumor and/or in the metastatic lymph node were randomized into FEMP, FEMP + LMS, or FEMP + PSK. The risk ratio was lower in the FEMP + PSK group compared to the FEMP group. In disease-free survival or overall survival, there was no significant difference between the three groups, however, the survival curve of the FEMP + PSK group tended to be better than that of the FEMP group(logrank, P = 0.0706; generalized Wilcoxon, P = 0.0739). Side effects were observed at a low incidence, but they were mild and tolerable. Immunochemotherapy using PSK improved the prognosis of patients with operable breast cancer with vascular invasion.
Invernizzi R, Bernuzzi S, Ciani D, Ascari E. Silymarine during maintenance therapy of acute promyelocytic leukemia.
Haemotologia Haematologica 1993 Sep-Oct;78(5):340-341. (Letter)
Israel L, Hajji O, Grefft-Alami A, Desmoulins D, Succari M, Cals MJ, Miocque M, Breau JL, Morere JF. [Vitamin A augmentation of the effects of chemotherapy in metastatic breast cancers after menopause. Randomized trial in 100 patients].
Ann Med Interne (Paris) 1985;136(7):551-554. [Article in French]
Abstract: Vitamin A was administered to randomly allocated patients in a group of 100 patients with metastatic breast carcinoma treated by chemotherapy. The daily doses (given indefinitely) ranged from 350,000 to 500,000 IU according to body weight. A significant increase in the complete response rate was observed. When subgroups determined by menopausal status were considered, it was observed that serum retinol levels were only significantly increased in the post-menopausal group on high dose Vitamin A. Response rates, duration of response and projected survival were only significantly increased in this subgroup. The therapeutic and biological implications of these findings are discussed.
Killestein J, Nelemans SA. [Therapeutic applications and biomedical effects of cannabinoids; pharmacological starting points].
Ned Tijdschr Geneeskd. 1997 Aug 30;141(35):1689-1693. (Review) [Article in Dutch]
Kodama J, Ikuhashi H, Hongo A, Mizutani Y, Miyagi Y, Yoshinouchi M, Kobashi Y, Okuda H, Kudo T. [Neoadjuvant chemotherapy for advanced cervical cancer].
Gan To Kagaku Ryoho 1999 Jan;26(1):89-92. [Article in Japanese]
Abstract: Twenty-five patients with advanced cervical cancer (IIb-IVa) were treated with neoadjuvant chemotherapy followed by radical hysterectomy or radiotherapy. According to the evaluation by MRI, complete response was achieved in 2 cases and partial response in 17 cases. Eventually the response rate was 76%. The response rate was higher in squamous cell carcinomas (85%) than adenocarcinomas or adenosquamous carcinomas (67%). The histological effect is superior in squamous cell carcinomas than adenocarcinomas or adenosquamous carcinomas. Radical hysterectomy was performed in 5 cases of 11 (45%) stage III-IVa cervical cancers. There was no correlation between tumor size and response to NAC. NAC therapy may be useful therapy in advanced cervical cancers, especially squamous cell carcinomas.
Kogure A, Ishii S, Kakefuda T, Aiura K, Arisawa Y, Kitagawa Y, Nakagawa M, Shirasugi N, Noga K. [A case of inoperable advanced gastric cancer remarkably responding to combined chemotherapy with UFT-E, MMC and PSK].
Gan To Kagaku Ryoho 1997 May;24(7):875-878. [Article in Japanese]
Abstract: A 55-year-old male consulted a local doctor with the complaint of epigastralgia. Examination of the upper gastrointestinal tract revealed gastric cancer (Borrmann Type II) and he was referred to our hospital for operation. A few lymph nodes were palpable in the left supraclavicular fossa, and the biopsy of those lymph nodes revealed metastatic adenocarcinoma. The CT scan of the abdomen showed enlargement of paraaortic lymph nodes. Then, the patient was determined inoperable (T3, N4, H02 P01, M1 stage IVb). He was treated as an outpatient with UFT-E (300 mg/day, orally), Krestin (PSK 3.0 g/day, orally) and Mitomycin C (MMC 6 or 8 mg once a week, intravenously repeated interval of 4 weeks). The total dose of UFT-E, PSK and MMC was 219 g, 1,095 g and 136 mg, respectively. One month later, lymph nodes in the supraclavicular fossa disappeared, and the lesion in the stomach completely responded. We have followed the patient for more than one year. He visits our the outpatient department and has kept working until now.
Kong Q, Lillehei KO. Antioxidant inhibitors for cancer therapy. Med Hypotheses 1998 Nov;51(5):405-409.
Abstract: Built-in cellular defense mechanisms play a major role in a tumor's protection against non-surgical antineoplastic therapies. Of these, the overexpression of antioxidants such as superoxide dismutase (SOD) may be the most important. Oxygen radicals are highly toxic, and have been implicated in various diseases, including carcinogenesis and aging. They produce a variety of pathological changes through lipid peroxidation and DNA damage. Therefore, treating free-radical-induced diseases with antioxidants has been an accepted therapeutic approach. Ironically, however, the underlying mechanism that most chemotherapeutic agents and ionizing radiation exert on tumor cell kill is not increased antioxidation but rather the production of more free radicals leading to irreversible tissue injury. A small increase in reactive oxygen species (ROS) following non-surgical antineoplastic therapies induces the expression of antioxidants such as SOD, but overproduction of ROS, conversely, exhausts the production of SOD and other adaptive antioxidant defenses. Based on these considerations, we hypothesize that the appropriate administration of antioxidant inhibitors and/or free-radical-generating compounds may be a useful strategy in the treatment of solid tumors.
Krivit W. Adriamycin cardiotoxicity amelioration by alpha-tocopherol. Am J Pediatr Hematol Oncol
1979 Summer;1(2):151-153.
Abstract: Adriamycin has become a potent member of the cancer chemotherapeutic program. However, the full utilization of adriamycin is limited by its cardiotoxicity. In experimental animals, alpha-tocopherol has been shown by some to ameliorate or prevent cardiac dysfunction without impairing antitumor effectiveness. During adriamycin therapy, future clinical research should consist of biochemical measurements of vitamin E in plasma, lipoperoxidation in red cells and platelets, while cars to indicate deficiency, should be considered as one method of ameliorating toxicity.
Kupin VJ. Eleutherococcus and Other Biologically Active Modifiers in Oncology. Moscow: Medexport, 1984.
Kupin VI, Polevaia EB, Sorokin AM. [Immunomodulating action of an Eleuterococcus extract in oncologic patients].
Sov Med 1987;(5):114-116. [Article in Russian]
Kurbacher CM, Wagner U, Kolster B, Andreotti PE, Krebs D, Bruckner HW. Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro.
Cancer Letters 1996 Jun 5;103(2):183-119.
Abstract: Utilizing a microplate ATP bioluminescence assay, two human breast carcinoma cell lines, MCF-7 and MDA-MB-231, were tested against doxorubicin (DOX), cisplatin (DDP), and paclitaxel (Tx) alone and in combination with ascorbic acid (Vit C). In both cell lines, Vit C exhibited cytotoxic activity at high concentrations (i.e. 10(2)-10(3) microM). Both cell lines also were resistant to DOX. MCF-7 was found to be DDP-resistant, MDA-MB-231 was moderately sensitive to DDP. Both cell lines were strongly sensitive to Tx. Vit C both at non-cytotoxic (1 microM) and moderately cytotoxic concentrations (10(2) microM) improved the cytotoxicity of DOX, DDP, and Tx significantly. Combination effects between Vit C and DDP or Tx were partly synergistic and partly additive or subadditive whereas a consistent synergism was found between Vit C and DOX. The mechanisms by which Vit C potentiates the cytostatics studied are yet unclear and should be evaluated further.
Labriola D, Livingston R. Possible interactions between dietary antioxidants and chemotherapy.
Oncology (Huntingt). 1999 Jul;13(7):1003-1008; discussion 1008, 1011-1012.
Abstract: Many patients treat themselves with oral antioxidants and other alternative therapies during chemotherapy, frequently without advising their conventional health care provider. No definitive studies have demonstrated the long-term effects of combining chemotherapeutic agents and oral antioxidants in humans. However, there is sufficient understanding of the mechanisms of action of both chemotherapeutic agents and antioxidants to predict the obvious interactions and to suggest where caution should be exercised with respect to both clinical decisions and study interpretation. This article will describe these potential interactions and areas of concern, based on the available data. It will also suggest several potential courses of action that clinicians may take when patients indicate that they are taking or plan to use alternative therapies.
Legha SS, Wang YM, Mackay B, Ewer M, Hortobagyi GN, Benjamin RS, Ali MK. Clinical and pharmacologic investigation of the effects of alpha-tocopherol on Adriamycin cardiotoxicity.
Ann NY Acad Sci 1982;393:411-418.
Abstract: Our data indicate that alpha-tocopherol used in an oral dose of 2 g/m2 daily results in a six- to eightfold increase of the vitamin E levels in serum. The occurrence of congestive heart failure in three patients and the observation of significant pathologic changes in endomyocardial biopsies in approximately half of the patients treated with a median cumulative adriamycin dose level of 550 mg/m2 indicate that alpha-tocopherol does not offer substantial protection against adriamycin-induced cardiac toxicity. The antitumor activity of the drug, however, is not compromised by the concomitant administration of the vitamin.
Lersch C, Zeuner M, Bauer A, Siemens M, Hart R, Drescher M, Fink U, Dancygier H, Classen M. Nonspecific immunostimulation with low doses of cyclophosphamide (LDCY), thymostimulin, and Echinacea purpurea extracts (Echinacin) in patients with far advanced colorectal cancers: Preliminary results.
Cancer Invest 1992;10(5):343-348.
Abstract: Outpatients (n = 15) with metastasizing far advanced colorectal cancers received immunotherapy consisting of low-dose cyclophosphamide (LDCY) 300 mg/m2 every 28 days i.v., thymostimulin 30 mg/m2, days 3-10 after low-dose cyclophosphamide i.m. once daily, then twice a week, and echinacin 60 mg/m2 together with thymostimulin i.m. All patients had had previous surgery and/or chemotherapy and had progressive disease upon entering the study. Two months after onset of therapy a partial tumor regression was documented in one and a stable disease in 6 other patients by abdominal ultrasonography, decrease of the tumor markers carcinoembryonic antigen (CEA), CA 19-9, CA 15-3, and/or chest roentgenography, which may also be attributed to the natural course of disease. Mean survival time was 4 months, 2 patients survived for more than 8 months. Immunotherapy was well tolerated by all patients without side effects.
Lersch C, Zeuner M, Bauer A, Siebenrock K, Hart R, Wagner F, Fink U, Dancygier H, Classen M. Stimulation of the immune response in outpatients with hepatocellular carcinomas by low doses of cyclophosphamide (LDCY), echinacea purpurea extracts (Echinacin) and thymostimulin.
Arch Geschwulstforsch 1990;60(5):379-383.
Lopez I, Goudou C, Ribrag V, et al. [Treatment of mucositis with vitamin E during administration of neutropenic antineoplastic agents].
Ann Med Interne (Paris) 1994;145(6):405-408. [Article in French]
Abstract: Mucositis represents one of the most frequent complications during chemotherapy or radiotherapy. Few studies have showed effective prevention against mucositis in this setting. In this randomized study, we tested the efficacy of vitamin E in the treatment of chemotherapy-induced mucositis. Twenty patients with malignant haemopathies were included; 19 patients were evaluable for the prevention of mucositis. Ten patients were treated with induction therapy for acute myelogenous leukaemia and 9 were treated with intensive therapy followed by autologous bone marrow transplantations. The severity of mucositis was evaluated according to World Health Organization classification. Our results showed that vitamin E may be of therapeutical value in the prevention of mucositis especially during induction therapy for acute myelogenous leukaemia.
McAnena OJ, Daly JM. Impact of antitumor therapy on nutrition. Surg Clin North Am
1986 Dec;66(6):1213-1228. (Review)
Abstract: Surgery, radiation, and chemotherapy can result in further deterioration in nutritional status in patients who are frequently malnourished as a consequence of their underlying malignancy. Many of the effects are transient, and patients who have a good performance status may exhibit minimal alterations in nutritional parameters during the course of treatment. However, antitumor treatment may enhance morbidity, and in some, it leads to mortality if patients are in poor nutritional status ab initio. Such malnourished patients must be recognized prior to initiation of treatment, and steps must be taken to maintain adequate nutrition. The known toxic effects of many cancer therapeutic regimens must be weighed against their potential benefits.
Mattes RD, Curran WJ Jr, Alavi J, Powlis W, Whittington R. Clinical implications of learned food aversions in patients with cancer treated with chemotherapy or radiation therapy.
Cancer 1992 Jul 1;70(1):192-200.
Mattes RD. Prevention of food aversions in cancer patients during treatment.
Nutr Cancer 1994;21(1):13-24.
Abstract: Food aversions are a common complication of cancer treatment. This study evaluated an approach for blocking the formation of aversions to dietary items in 209 cancer patients treated with chemo- and/or radiotherapy. Patients were exposed to a sensory stimulus (fruit beverage, halava, odor) before initial treatments to provide a target for aversion formation, thereby sparing dietary items. Patients who developed an aversion to the "scapegoat" stimulus experienced a statistically significant 30% reduction in dietary aversion formation relative to patients without a scapegoat aversion or those not exposed to the scapegoat. The most effective scapegoat was the beverage, probably because it was consumed in greatest quantity. Exposure of patients to a "scapegoat" food or beverage just before chemo- and, probably, radiotherapy can markedly reduce the incidence of treatment-related aversions to foods in the patients' customary diet.
Meyer K, Schwartz J, Crater D, Keyes B. Zingiber officinale (ginger) used to prevent 8-Mop associated nausea.
Dermatol Nurs 1995 Aug;7(4):242-244.
Abstract: Patients undergoing photopheresis are required to ingest the drug 8-MOP as part of their treatment. This drug causes nausea as a side effect. Ginger taken prior to 8-MOP may substantially reduce this side effect. This study compared patients' nausea when taking 8-MOP with and without ginger.
Mills EED. The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis.
Brit J Cancer 1988 Apr;57(4):416-417.
Mitomi T, Kyoji-Ogoshi. [Clinical study of PSK as an adjuvant immunochemotherapeutic agent against gastric cancer].
Gan To Kagaku Ryoho 1986 Aug;13(8):2532-2537. [Article in Japanese]
Abstract: The effects of PSK in combination with Mitomycin C, Adriamycin and Tegafur were studied in 168 patients who underwent gastrectomy for gastric cancer. The study group receiving PSK showed improved survival and there was a significant difference in the estimated survival. An improved survival rate was also shown at stages III and IV, in the group given an FAM regimen and in the group with well differentiated adenocarcinoma.
Mitomi T, Tsuchiya S, Iijima N, et al. Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. The Cooperative Study Group of Surgical Adjuvant Immunochemotherapy for Cancer of Colon and Rectum (Kanagawa).
Dis Colon Rectum 1992;35:123-130.
Monokhov BV. [Influence of the liquid extract from the roots of Eleutherococcus.]
Vopr Onkol 1965;11(12):60-63. [Article in Russian]
Ng TB. A review of research on the protein-bound polysaccharide (polysaccharopeptide, PSP) from the mushroom Coriolus versicolor (Basidiomycetes: Polyporaceae).
Gen Pharmacol 1998 Jan;30(1):1-4. (Review)
Abstract: 1. Protein-bound polysaccharides, designated as PSK and PSP, have been isolated from the CM-101 strain and the COV-1 strain, respectively, of the mushroom Coriolus versicolor. This article aims at summarizing existing research findings about PSP since information on PSK is well documented. 2. PSP possesses a molecular weight of approximately 100 kDa. Glutamic and aspartic acids are abundant in its polypeptide component, whereas its polysaccharide component is made up of monosaccharides with alpha-1,4 and beta-1,3 glucosidic linkages. The presence of fucose in PSK and rhamnose and arabinose in PSP distinguishes the two protein-bound polysaccharides, which are otherwise chemically similar. 3. PSP is classified as a biological response modifier. It induces, in experimental animals, increased gamma-interferon production, interleukin-2 production, and T-cell proliferation. It also counteracts the depressive effect of cyclophosphamide on white blood cell count, interleukin-2 production and delayed-type hypersensitivity reaction. Its antiproliferative activity against tumor cell lines and in vivo antitumor activity have been demonstrated. A small peptide with a molecular weight of 16-18 kDa originating from PSP has been produced with antiproliferative and antitumor activities. 4. PSP administered to patients with esophageal cancer, gastric cancer and lung cancer, and who are undergoing radiotherapy or chemotherapy, helps alleviate symptoms and prevents the decline in immune status.
Ogoshi K, Mitomi T. [Clinical effects of PSK on esophageal and gastric cancer patients and usefulness of serum levels of glycoproteins and HLA antigens as prognostic indicators]. Nippon Geka Gakkai Zasshi
1989 Sep;90(9):1443-1446. [Article in Japanese]
Abstract: This study was carried out to evaluate whether the preoperative levels of serum glycoproteins (CEA, SCC, TPA, IAP, ACT, ASP and sialic acid) and HLA antigens (class I and II) could be potential aids in the selection of suitable gastric and esophageal cancer patients for postoperative adjuvant immunotherapy of PSK. Gastric cancer patients underwent gastrectomy and received postoperative adjuvant chemotherapy (MMC, FT and ADR) with or without PSK. One hundred and forty esophageal cancer patients in cooperative study groups (organizing chairman; Dr. Hiroshi Satoh) underwent esophagectomy and received postoperative adjuvant radiotherapy and chemotherapy (FT, BLM) with or without PSK. The efficacy of PSK was recognized in the patients with normal levels of all glycoproteins in gastric cancer, and with normal levels of CEA or SCC or TPA and abnormal levels of one or more APRs in both gastric and esophageal cancer, and with positive HLA-B40 antigen. The combination of tumor-associated factors, such as CEA, SCC and TPA and various non-specific reactants such as APRs was useful as a prognostic indicator. In addition, some of HLA antigens were also valuable. The pretreatment levels of glycoproteins and HLA antigens have potential aids in the selection of patients with gastric and esophageal cancer for PSK treatment.
Ogoshi K, Satou H, Isono K, Mitomi T, Endoh M, Sugita M. Immunotherapy for esophageal cancer. A randomized trial in combination with radiotherapy and radiochemotherapy. Cooperative Study Group for Esophageal Cancer in Japan.
Am J Clin Oncol 1995 Jun;18(3):216-222.
Abstract: We investigated the effect of multimodal therapy in 187 patients with esophageal cancer. All patients were followed up over a period of 5 years. Among the 187 patients, 174 (93.1%) eligible patients with biopsy-proved esophageal squamous cell carcinoma underwent esophagectomy and were randomly assigned to receive radiotherapy (RT) with or without protein-bound polysaccharide (PSK), or RT plus chemotherapy (CT) with or without PSK. The 5-year survival rates of patients with RT, RT+PSK, RT+CT and RT+CT+PSK were 40.0%, 42.3%, 29.1% and 37.2%, respectively. There was a tendency for longer survival on PSK, but statistical significance was not reached (RT+CT group versus RT+CT+PSK group: log-rank and generalized Wilcoxon tests, P = .1930, P = .1034). However, Cox multivariate regression analysis indicated that postoperative therapy with or without PSK was the most significant prognostic factor for patients receiving RT+CT and for the eligible patients. These results indicate that PSK may have a beneficial effect on esophageal carcinoma when given in combination with CT+RT.
Pace JC. Oral ingestion of encapsulated ginger and reported self care actions for the relief of chemotherapy-associated nausea and vomiting.
Dissertation Abstr Internat 1987;8:3297.
Pandalai PK, Pilat MJ, Yamazaki K, Naik H, Pienta KJ. The effects of omega-3 and omega-6 fatty acids on in vitro prostate cancer growth.
Anticancer Res 1996 Mar-Apr;16(2):815-820.
Dietary intake of essential fatty acids (EFA) may play a role in prostate cancer cell proliferation. Epidemiological studies have demonstrated that men whose dietary intake is high in omega-3 fatty acid (FA) composition have a lower incidence of clinical prostate cancer, suggesting that external factors such as diet may play an important role in development and growth of prostate cancer. Furthermore, in prostate cancer cell lines, omega-6 and omega-3 FAs have demonstrated promotional and inhibitory effects respectively. To investigate the effects of dietary fats on nontumorigenic prostate cell growth we conducted in vitro studies with human metastatic PC-3, LNCaP and TSU prostate cell lines, the rat metastatic Mat-Ly-Lu cell line and rat non-metastatic epithelial cell lines EPYP1, EPYP2 and EPYP3. Cell lines were treated with linoleic acid (LA), an omega-6 FA (n-6), as well as linolenic (LLA) and eicosapentaenoic (EPA) acids, which are both omega-3 FAs (n-3). All cell lines were treated with 10% and 0.5% serum supplemented media plus fatty acid for comparison. Our results demonstrate that linoleic acid(n-6) has promotional effects at doses of 1-100ng/ml in all cell lines with the exception of EPYPl. Experiments with linolenic acid (n-3) demonstrated consistent growth promotion in all cell lines examined with the exception of the EPYP2 cell line in which there was no significant effect. EPA had no effect in culture media supplemented with 10% serum, while in media containing 0.5% serum this FA demonstrated significant promotion in all human lines. Previous studies have indicated that EPA should inhibit human prostate cancer growth in vitro, however our results demonstrated promotion at low concentrations (lng/ml). At higher concentrations, EPA did inhibit prostate cell growth. These data indicate low levels of dietary fat, regardless of composition, may play a role in prostate cancer proliferation and could be an avenue for therapeutic intervention.
Robert J. Multidrug resistance in oncology: diagnostic and therapeutic approaches.
Eur J Clin Invest. 1999 Jun;29(6):536-545. (Review)
Sacks PG, Harris D, Chou T-C. Modulation of growth and proliferation in squamous cell carcinoma by retinoic acid: A rationale for combination therapy with chemotherapeutic agents.
Int J Cancer 1995 May 4;61(3):409-415.
Abstract: We have previously shown that beta-all trans retinoic acid (RA) inhibits macrocellular growth of a multicellular tumor spheroid model for squamous carcinoma, as measured by spheroid size, but allows for continuing DNA synthesis and cell cycle progression, the two being reconciled by a cell death effect. DNA synthesis in the presence of growth inhibition suggested a rationale for examining combination chemotherapy with RA-inhibited cells. To this aim, we have extended this observation to a series of 8 squamous carcinoma cell lines. Cells were treated with 1 microM RA for 7 days and cell growth parameters monitored. Although growth inhibition ranged from 0% (A431) to approx. 80% (MDA 886Ln), [3H]-thymidine incorporation (cpm/microgram protein) and percent S-phase (by flow cytometry) in 7-day RA-treated cells was equal or higher than in their control vehicle-treated cells in 7/8 SCC cell lines. Thus RA-induced growth inhibition is not just cytostasis. Combination therapy was examined with MDA 886Ln, MDA 686Ln, 1483 and A431 cells pre-treated for 7 days with 1 microM RA followed by cisplatin or 5-fluorouracil treatment. An increased effectiveness for the combination was shown using 5-day tetrazolium dye (MTT) growth assays when cells were growth-inhibited by RA. Computerized analysis of data using median-effect and isobologram techniques indicated that the interaction of RA with these chemotherapeutic agents was synergistic. With squamous carcinoma, RA treatment inhibits growth while allowing for continuing DNA synthesis, and these RA-treated, growth-inhibited cells exhibit increased sensitivity to chemotherapeutic agents.
Salignik R, et al. Avoiding vitamins A and E may improve cancer therapy. 39th Annual meeting of the American Society for Cell Biology, Dec 11-15th, 1999.
Abstract: Apoptosis, or programmed cell death, eliminates selectively precancerous and cancerous cells. Since reactive oxygen species (ROS) act as essential mediators of apoptosis, antioxidants inhibit this protective form of cell death. Most anticancer drugs kill cancer cells by apoptosis and antioxidants interfere with their anticancer effect. Since depletion of ROS decreases apoptosis, we reasoned that increasing the level of ROS might enhance apoptotic death of cancer cells and inhibit thereby tumor growth. Here, using a defined transgenic brain tumor model, we test the impact of feeding an antioxidant depleted diet, capable of increasing ROS accumulation, on apoptosis and tumor growth. Dramatically increased apoptosis occurs within tumors in antioxidant-depleted mice, but not in normal tissues. Detectably increased oxidant stress indicates that the likely mechanism of enhanced tumor apoptosis is via a rise in ROS. Tumor growth is significantly inhibited in mice fed an antioxidant-depleted diet. In clear contrast, an oxidant-enriched diet had no impact on tumor growth.
Saji S, Sakamoto J, Teramukai S, Kunieda K, Sugiyama Y, Ohashi Y, Nakazato H. Impact of splenectomy and immunochemotherapy on survival following gastrectomy for carcinoma: covariate interaction with immunosuppressive acidic protein, a serum marker for the host immune system. Tumor Marker Committee for the Study Group of Immunochemotherapy with PSK for Gastric Cancer.
Surg Today 1999;29(6):504-510.
Abstract: The role of the spleen in tumor immunology is still controversial in that it can either enhance or suppress the antitumor immune response depending on the tumor-bearing host. To clarify this biphasic effect of the spleen, a clinical evaluation of splenectomy in conjunction with immunotherapy and the host immune status was performed in gastric cancer patients. The effect of splenectomy and immunotherapy in 253 gastric cancer patients enrolled in a prospective randomized trial (SIP) was analyzed using the Cox's proportional hazards model in terms of the covariate interaction of the preoperative immunosuppressive acidic protein (IAP) level. In patients with high IAP levels (>580 microg/ml) with predicted negative antitumor immune reactions, splenectomy improved the prognosis. In patients with lower IAP values, conversely, the preservation of the spleen and immunotherapy demonstrated a significant benefit to survival. The spleen was shown to have a biphasic activity in terms of its antitumor immune response depending on the IAP level of the patient. The effect of immunotherapy is significantly influenced by the activity of spleen cells. The preoperative IAP level is therefore considered to be a possible indicator for the effectiveness of splenectomy and immunotherapy in curatively resected gastric cancer patients.
Scambia G, De Vincenzo R, Ranelletti FO, Panici PB, Ferrandina G, D'Agostino G, Fattorossi A, Bombardelli E, Mancuso S. Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin.
Eur J Cancer 1996 May;32A(5):877-882.
Abstract: The aim of this study was to test the antiproliferative activity of silybin, a flavonoid, on human ovarian and breast cancer cell lines. Since flavonoids are thought to act through Type II oestrogen binding sites (Type II EBS), silybin binding to Type II EBS was also examined. Silybin, used in concentrations from 0.1 to 20 microM, exerted a dose-dependent growth inhibitory effect on OVCA 433, A2780 parental and drug-resistant ovarian cancer cells, and MCF-7 doxorubicin (DOX)-resistant breast cancer cells (IC50 = 4.8-24 microM). Both L and D diastereoisomers of silybin were effective in inhibiting A2780 WT cell growth (IC50 = 14 and 20 microM, respectively). Flow cytometry revealed that silybin decreased the percentage of cells in the S and G2-M phases of the cell cycle with a concomitant increase in cells in the G0-G1 phase. Silybin was able to compete with [3H]E2 for nuclear but not cytosolic Type II EBS. Its affinity parallels its efficacy in inhibiting cell proliferation. Furthermore, silybin (0.1 and 1 microM) potentiates the effect of cisplatin (CDDP) (0.1-1 micrograms/ml) in inhibiting A2780 WT and CDDP-resistant cell growth. Similar results were obtained on MCF-7 DOX-resistant cells when silybin (0.1 microM) was associated with doxorubicin (0.1-10 micrograms/ml). As assessed by the Berembaum isobole method, the effect of silybin-CDDP and silybin-DOX combinations results in a synergistic action. Using the 'stem cell assay' described by Hamburger and Salmon [Science 1977, 197, 461-463], we found that silybin exerted a dose-dependent inhibition of clonogenic efficiency of cells derived from three ovarian tumours (IC50 = 7.4, 4 and 6.4 microM, respectively). Since CDDP and DOX are the two most commonly used drugs for gynaecological tumours, the clinical application of silybin is currently under investigation in our institute.
Schwartz RH, Beveridge RA. Marijuana as an antiemetic drug: how useful is it today? Opinions from clinical oncologists.
J Addict Dis 1994;13(1):53-65.
Abstract: OBJECTIVE: To determine the antiemetic drug preferences of practicing adult oncologists and to estimate the frequency of use of marijuana smoke as an antiemetic agent. DESIGN: Identical mailed questionnaire surveys on antiemetic preferences, distributed prior to approval of ondansetron. SAMPLE: Two groups of practicing clinical adult oncologists were surveyed. The first group (N = 120) consisted of every twentieth board-certified, American member of the American Society of Clinic Oncology culled from the 1990 ASCO membership directory in alphabetical order. The second group (N = 60) consisted of every adult clinical oncologist in metropolitan Washington, D.C. MEASUREMENTS/RESULTS: Completed surveys were returned by 141 (78%) physicians; the responses from both groups were almost identical (Wilcoxon Rank Sum Test). Marijuana (either as marijuana smoke or oral tetrahydrocannabinol) ranked ninth in order of preference for the treatment of mild to moderate nausea and vomiting, and sixth for the treatment of more severe symptoms induced by chemotherapy. Most (94 or 65%) respondents reported having prescribed marijuana or oral THC 10 times or less; only 5 (3.5%) had prescribed such drugs more than 100 times which represented for them about 1% of their average lifetime clinical patient load. The respondents who had prescribed marijuana in any form thought that it had effectively relieved post-chemotherapy nausea or vomiting in 50% of patients. Unpleasant adverse effects were estimated to have occurred in 25% of treated patients. Only 8 (6%) respondents indicated that they would prescribe marijuana much more frequently--if there were no legal barriers associated with its medical use. CONCLUSION: Marijuana in any form was believed to be efficacious for 50% of patients with pre- or post-chemotherapy nausea or vomiting. However, one of four patients who received it complained of bothersome adverse effects. At the time of the study, cannabis was prescribed or recommended relatively infrequently by American clinical oncologists (i.e., those who actually prescribed chemotherapy). Even if it was freely available and restrictions on its use liberalized, smokeable marijuana, according to responses given on this survey, would not be used much more frequently by American oncologists.
Sharma SS, Gupta YK. Reversal of cisplatin-induced delay in gastric emptying in rats by ginger (Zingiber officinale).
J Ethnopharmacol 1998 Aug;62(1):49-55
Abstract: Cisplatin causes nausea, vomiting and inhibition of gastric emptying. We have demonstrated the antiemetic effect of the acetone and ethanolic extract of ginger (Zingiber officinale, Roscoe, Zingiberacae) against cisplatin-induced emesis in dogs. In the present study, the acetone and 50% ethanolic extract of ginger in the doses of 100, 200 and 500 mg/kg (p.o.) and ginger juice, in the doses of 2 and 4 ml/kg, were investigated against cisplatin effect on gastric emptying in rats. All three ginger preparations significantly reversed cisplatin-induced delay in gastric emptying. The ginger juice and acetone extract were more effective than the 50% ethanolic extract. The reversal produced by the ginger acetone extract was similar to that caused by the 5-HT3 receptor antagonist ondansetron; however, ginger juice produced better reversal than ondansetron. Therefore, ginger, an antiemetic for cancer chemotherapy, may also be useful in improving the gastrointestinal side effects of cancer chemotherapy.
Spingarn A, Sacks PG, Kelley D, Dannenberg AJ, Schantz SP. Synergistic effects of 13-cis retinoic acid and arachidonic acid cascade inhibitors on growth of head and neck squamous cell carcinoma in vitro.
Otolaryngol Head Neck Surg 1998 Feb;118(2):159-164.
Abstract: Products of arachidonic acid metabolism can influence normal and malignant cell growth. In vivo, inhibitors of arachidonic acid metabolism have been associated with inhibition of tumor growth, including head and neck squamous cell carcinoma (HNSCC). This has not been evaluated extensively in vitro in an HNSCC model. Therefore we investigated the effects of several arachidonic acid cascade inhibitors (AACIs) (indomethacin, curcumin, phenidone, nordihydroguaiaretic acid, 5,8,11,14-eicosatetraynoic acid, and 13-cisretinoic acid) on the growth of two HNSCC cell lines (MDA 886Ln and 1483). We found that AACIs caused dose-dependent growth inhibition of both cell lines. In an effort to inhibit HNSCC cell growth at lower concentrations of these drugs, we evaluated the effects of a variety of AACIs in combination with 13-cis retinoic acid. We observed synergistic growth inhibition when the drugs were used in all combinations, with the exception of indomethacin. These results suggest that AACIs may have some utility in the direct treatment of HNSCC, and a strategy combining 13-cis retinoic acid with other AACIs may prove to be even more effective.
Taper HS, de Gerlache J, Lans M, Roberfroid M. Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment.
Int J Cancer 1987 Oct 15;40(4):575-579.
Abstract: The influence on the survival of ascitic liver tumor (TLT)-bearing mice of combined vitamins C and K3 administered before or after a single i.p. dose of 6 different cytotoxic drugs, all commonly used in human cancer therapy, was investigated. Combined i.p. administration of these vitamins produced a distinct chemotherapy-potentiating effect for all drugs examined, especially when injected before chemotherapy. This potentiating treatment did not increase the general and organ toxicity that accompanies cancer chemotherapy. The possible generation of peroxides followed by membrane lipid alteration, DNase activation and DNA destruction by combined vitamin C and K3 in catalase-deficient cancer cells might be involved in the mechanisms of this selective potentiation.
Tisdale MJ. Inhibition of lipolysis and muscle protein degradation by EPA in cancer cachexia.
Nutrition 1996 Jan;12(1 Suppl):S31-33.
Abstract: Depletion of muscle and adipose tissue in cancer cachexia appears to arise not only from decreased food intake but also from the production of catabolic factors by certain tumours. Experiments with the cachexia-inducing MAC16 tumour in mice showed that when part of the carbohydrate calories were replaced by fish oil, host body weight loss was inhibited. The effect occurred without an alteration of either the total calorie consumption or nitrogen intake. Instead, one of the polyunsaturated fatty acids (PUFA) in fish oil, eicosapentaenoic acid (EPA), was found directly to inhibit tumour-induced lipolysis. The effect was structurally specific, as two related PUFA, docosahexaenoic acid (DHA) and gamma-linolenic acid (GLA), were without effect. The antilipolytic effect of EPA arose from an inhibition of the elevation of cyclic AMP in adipocytes in response to the lipid mobilizing factor. The increased protein degradation in the skeletal muscle of cachectic animals was also inhibited by EPA. This effect was due to the inhibition of the rise in muscle prostaglandin E2 in response to a tumour-produced proteolytic factor by EPA. Thus, reversal of cachexia by EPA in this mouse model results from its capacity to interfere with tumour-produced catabolic factors. Similar factors have been detected in human cancer cachexia.
Tisdale MJ. Wasting in cancer. J Nutr 1999 Jan;129(1S Suppl):243S-246S. (Review)
Progressive weight loss is a common feature of many types of cancer and is responsible not only for a poor quality of life and poor response to chemotherapy, but also a shorter survival time than is found in patients with comparable tumors without weight loss. Although anorexia is common, a decreased food intake alone is unable to account for the changes in body composition seen in cancer patients, and increasing nutrient intake is unable to reverse the wasting syndrome. Although energy expenditure is increased in some patients, cachexia can occur even with a normal energy expenditure. Various factors have been investigated as mediators of tissue wasting in cachexia. These include cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interferon-gamma (IFN-gamma) and leukemia inhibitory factor (LIF), as well as tumor-derived factors such as lipid mobilizing factor (LMF) and protein mobilizing factor (PMF), which can directly mobilize fatty acids and amino acids from adipose tissue and skeletal muscle respectively. Induction of lipolysis by the cytokines is thought to result from an inhibition of lipoprotein lipase (LPL), although clinical studies provide no evidence for an inhibition of LPL in the adipose tissue of cancer patients. Instead there is an increased expression of hormone sensitive lipase, the enzyme activated by LMF. Protein degradation in cachexia is associated with an increased activity of the ATP-ubiquitin-proteasome pathway. The biological activity of both the LMF and PMF was shown to be attenuated by eicosapentaenoic acid (EPA). Clinical studies show that this polyunsaturated fatty acid is able to stabilize the rate of weight loss and adipose tissue and muscle mass in cachectic patients with unresectable pancreatic cancer. Knowledge of the mechanism of cancer cachexia should lead to the development of new therapeutic agents.
Toi M, Hattori T, Akagi M, Inokuchi K, Orita K, Sugimachi K, Dohi K, Nomura Y, Monden Y, Hamada Y, et al. Randomized adjuvant trial to evaluate the addition of tamoxifen and PSK to chemotherapy in patients with primary breast cancer.
Cancer 1992 Nov 15;70(10):2475-2483.
Abstract: BACKGROUND. A randomized adjuvant trial was conducted from October 1982 to January 1985 to evaluate the addition of tamoxifen (TAM) to combination chemotherapy with perioperative mitomycin C (MMC) and ftorafur (FT) for patients with estrogen receptor (ER)-positive tumors and the addition of PSK, a biologic response modifier, to MMC+FT chemotherapy for patients with ER-negative tumors in operable Stage IIA, IIB, and IIIA cancer. The doses used were 20 mg of oral TAM daily, 600 mg of oral FT daily, and 3 g of oral PSK daily for 2 years. Intravenous MMC (13 mg/m2) was given on the day of operation. METHODS. A total of 967 patients were entered and randomized by stratification based on ER status and staging (1978 International Union Against Cancer [UICC] criteria at the time of trial execution). Of 967 patients, 914 (94.5%) were evaluable. At 5-year follow-up, significant prolonged overall survival (OS) and relapse-free survival (RFS) times were seen with the addition of TAM in patients with ER-positive and Stage IIIA T3N0 cancer (1987 UICC-American Joint Committee on Cancer [AJCC] criteria); however, no significant survival benefit from TAM was seen in patients with ER-positive and Stage IIA T2N1 cancer. There was no significant difference between regimens, with or without PSK, in patients with ER-negative disease. RESULTS. Results of subset analyses suggested a benefit from TAM in postmenopausal patients with ER-positive and Stage IIA T2N1 cancer and a benefit from PSK in patients with node-negative, ER-negative, and Stage IIA T2N1 cancer. CONCLUSIONS. The 5-year results of the current trial showed a survival advantage by the addition of TAM to chemotherapy in patients with ER-positive and Stage IIIA T3N0 cancer.
Wadleigh RG, Redman RS, Graham ML, Krasnow SH, Anderson A, Cohen MH. Vitamin E in the treatment of chemotherapy-induced mucositis.
Am J Med 1992 May;92(5):481-484.
Abstract: PURPOSE: To determine the efficacy of vitamin E in the treatment of chemotherapy-induced mucositis in patients with malignancy. PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled study was performed to evaluate the efficacy of topical vitamin E in the treatment of oral mucositis in patients receiving chemotherapy for various types of malignancy. A total of 18 patients, 17 of whom had solid tumors and one with acute leukemia, were included in this study. Lesions were observed daily prior to and 5 days after topical application of either vitamin E or placebo oil. RESULTS: Six of nine patients receiving vitamin E had complete resolution of their oral lesions. In eight of nine patients who received placebo, complete resolution of their oral lesions was not observed. This difference is statistically significant (p = 0.025 by Fisher's exact test). No toxicity was observed in this study. CONCLUSION: These results suggest that vitamin E may be an effective therapy in patients with chemotherapy-induced mucositis.
Wagdi P, Fluri M, Aeschbacher B, Fikrle A, Meier B. Cardioprotection in patients undergoing chemo- and/or radiotherapy for neoplastic disease. A pilot study.
Jpn Heart J 1996 May;37(3):353-359.
Abstract: OBJECTIVES: To assess the cardioprotective efficiency of an antioxidant regimen (vitamins E, C and N-acetylcysteine) in patients receiving high dose chemo- and/or radiotherapy for malignant disease. METHODS: Prospective, placebo controlled, randomized and double blinded pilot study involving 13 patients receiving chemotherapy and 12 patients receiving radiotherapy. RESULTS: In patients receiving antioxidants, left ventricular ejection fraction did not change (63 +/- 4% to 63 +/- 4%). In the placebo group, ejection fraction changed from 67 +/- 6% to 61 +/- 4% (p = 0.03). No patient in the antioxidant group and 6/13 (46%) patients in the placebo group showed a fall of > 10% in the left ventricular ejection fraction. In the chemotherapy group, the left ventricular ejection fraction changed from 62% (+/- 2) to 63% (+/- 2) in the patients treated with antioxidants (ns) and from 63% (+/- 5) to 61% (+/- 5) in patients treated with placebo (ns). No patient showed a significant fall in ejection fraction in the antioxidant group, whereas 2/7 (29%) in the placebo group showed a reduction > or = 10%. In the radiotherapy group, left ventricular ejection fraction did not change 64% (+/- 6) to 64% (+/- 5) in patients treated with antioxidants (ns) and changed from 70% (+/- 8) to 60% (+/- 4) in patients treated with placebo (p = 0.008). No patient in the antioxidant group, but 4/6 (66%) patients in the placebo group showed a fall of > or = 10% in ejection fraction. CONCLUSION: The small number of patients in the study precludes a definitive statement. The preliminary results however suggest efficient cardioprotection by this nontoxic and inexpensive antioxidant combination, so larger studies are warranted for confirmation.
Weijl NI, Hopman GD, Wipkink-Bakker A, Lentjes EG, Berger HM, Cleton FJ, Osanto S. Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients. Ann Oncol
1998 Dec;9(12):1331-1337.
Abstract: BACKGROUND: Antioxidants protect the body against cellular oxidative damage and thus some of the adverse effects induced by cisplatin and other cytostatic drugs. PATIENTS AND METHODS: The effect of cisplatin-combination chemotherapy on concentrations of plasma antioxidants was studied in 36 cancer patients, including osteosarcoma and testicular carcinoma patients. RESULTS: Eight to 15 days after the start of each cytostatic drug infusion concentrations of various plasma antioxidants were measured and compared to pretreatment values: vitamin C and E, uric acid and ceruloplasmin levels fell significantly (P < 0.01-0.005) and returned to baseline levels before the start of the next chemotherapy cycle. Levels of the antioxidants bilirubin albumin and the ratio vitamin E/cholesterol + triglycerides measured three weeks after the start of chemotherapy significantly decreased compared to pretreatment levels and remained low thereafter (P < 0.001-0.002). Dietary intake of antioxidants and anthropometric measurements, evaluated in 14 patients did not change during the whole treatment period. CONCLUSIONS: Cisplatin-combination chemotherapy induces a fall in plasma antioxidant levels, that may reflect a failure of the antioxidant defense mechanism against oxidative damage induced by commonly used anticancer drugs. This probably results from consumption of antioxidants caused by chemotherapy induced-oxidative stress as well as renal loss of water-soluble, small molecular weight antioxidants such as uric acid.
Weijl NI, Cleton FJ, Osanto S. Free radicals and antioxidants in chemotherapy-induced toxicity.
Cancer Treatment Rev 1997 Jul;23(4):209-240 (Review)
Wigmore SJ, Ross JA, Falconer JS, Plester CE, Tisdale MJ, Carter DC, Fearon KC. The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer.
Nutrition 1996 Jan;12(1 Suppl):S27-30.
Abstract: Cachexia is common in patients with pancreatic cancer and has been associated with persistent activation of the hepatic acute phase response and increased energy expenditure. Fatty acids have been shown to have anticachectic effects in animal models and to reduce inflammatory mediators in healthy subjects and patients with chronic inflammatory disease. Eighteen patients with unresectable pancreatic cancer received dietary supplementation orally with fish oil capsules (1 g each) containing eicosapentaenoic acid 18% and docosahexaenoic acid 12%. Anthropometric measurement, body composition analysis, and measurement of resting energy expenditure and serum C-reactive protein were performed before and after supplementation with a median of 12 g/day of fish oil. Patients had a median weight loss of 2.9 kg/month (IQR 2-4.6) prior to supplementation. At a median of 3 months after commencement of fish oil supplementation, patients had a median weight gain of 0.3 kg/month (IQR 0-0.5) (p < 0.002). Changes in weight were accompanied by a temporary but significant reduction in acute phase protein production (p < 0.002) and by stabilisation of resting energy expenditure. This study suggests a component fish oil, perhaps EPA, merits further investigation in the treatment of cancer cachexia.
Yokoe T, Iino Y, Takei H, Horiguchi J, Koibuchi Y, Maemura M, Ohwada S, Morishita. HLA antigen as predictive index for the outcome of breast cancer patients with adjuvant immunochemotherapy with PSK. Anticancer Res
1997 Jul-Aug;17(4A):2815-2818.
Abstract: We demonstrated that the prognosis of breast cancer patients who received adjuvant immunochemotherapy with Krestin (PSK) showed a tendency to be better than that of breast cancer patients receiving chemotherapy only. We retrospectively investigated the usefulness of HLA typing for selecting patients to receive adjuvant immuno-chemotherapy with PSK. One hundred and thirty-four patients with operable breast cancer were typed as HLA-A, -B, -C by a lymphocytotoxicity test. Patients without vascular invasion had no adjuvant therapy (NA group). Patients with vascular invasion in the tumor and/or in the metastatic lymph node were randomized into two groups. In group 1 (FEMP only), a combination chemotherapy of 100 mg of 5-fluorouracil (F), 50 mg of cyclophosphamide (E), 2 mg of mitomycin C (M), and 5 mg of predonisolone (P) was orally administered daily for 28 days (one course). In group 2 (FEMP+PSK), FEMP and 3.0 g of PSK were orally administered for 28 days (one course). Two courses a year of these agents were given for five years in both groups. Each group (NA, FEMP, FEMP+PSK) was stratified by the presence of HLA B40 type (B40(+)) or not (B40(-)). Five- and 10-year disease-free survival (DFS) rates (93%, 80%, respectively) of patients with B40(+) seemed to be better than those (83% and 51%) of patients with B40(-). In the NA group, 5- and 10-year DFS were 100% and 71% in patients with B40(+), 92% and 76% in those with B40(-), respectively. In the FEMP group (chemotherapy only), 5- and 10-year DFS of patients with B40(+) were both 84%. These were not statistically significant compared with those (82% and 33%) of patients with B40(-). On the other hand, in the FEMP+PSK group, 5- and 10-year DFS of patients with B40(+) were both 100%, and those of patients with B40(-) were 76% and 55%, respectively. DFS of patients with B40(+) was significantly better than that of patients with B40(-). It is concluded that HLA typing may be a predictive index in determining the use of immunochemotherapy combined with PSK for patients with operable breast cancer.